Histone H2A and H2AX are ubiquitinated in response to DNA damage and subsequently recruit repair and signaling factors and inhibit transcription at damaged loci. Unchecked histone ubiquitination could potentially lead to aberrant sequestration of DNA repair proteins or transcriptional silencing. Ring finger protein 168 (RNF168) is an E3 ubiquitin ligase that amplifies histone ubiquitin conjugates at sites of DNA damage, but the mechanisms that prevent RNF168-mediated ubiquitination from spreading to undamaged chromatin are unknown. Gudjonsson and colleagues generated cells stably expressing GFP-labeled RNF168 and performed an siRNA screen to identify genes required to prevent GFP accumulation. Two other E3 ubiquitin ligases, thyroid hormone receptor interactor 12 (TRIP12) and ubiquitin protein ligase E3 component n-recognin 5 (UBR5), were implicated in the regulation of RNF168, which determined the cellular capacity to ubiquitinate histones. Simultaneous knockdown of TRIP12 and UBR5 had an additive effect on the accumulation of both RNF168 and ubiquitin-sensing DNA damage response components such as 53BP1 and BRCA1. Intriguingly, increased recruitment of repair and signaling factors due to elevated RNF168 levels appeared to confer a selective advantage, as hyperaccumulation of RNF168 following TRIP12 or UBR5 depletion led to faster clearance of DNA damage foci, increased efficiency of both nonhomologous endjoining and homology-directed repair, and improved short-term survival after irradiation. Consistent with this possibility, unusually large 53BP1 foci were observed in multiple human papillomavirus (HPV)–positive tumor sections and were associated with markedly elevated levels of RNF168. Given that TRIP12 and UBR5 have been found to be mutated in some cancers, overproduction of RNF168 might be a mechanism to increase DNA repair efficiency and promote survival in tumor cells.